Effects of Angiotensin II on sustained outward currents in rat ventricular myocytes

We investigated the effects of angiotensin II (Ang II) on the sustained outward current (I-sus) and action potential of rat ventricular myocytes using the whole-cell patch-clamp technique. Ang II at 30 nMsimilar to3 muM inhibited I-sus with an IC50 of 240 nM, a Hill coefficient of 1.0 and maximum inhibition of 19.4%. Ang II-mediated inhibition of I-sus was voltage independent, was due to a decrease in the K+ current and was abolished by the Ang II type-I (AT(1)) receptor blocker, valsartan. The protein kinase C (PKC) inhibitors PKC19-36 or calphostin C, abolished Ang II-mediated inhibition of I-sus. In contrast, pretreatment with the protein kinase A (PKA) inhibitor PKA6-22 (100 muM) significantly enhanced the suppression of I-sus by 1 muM Ang II: (33.7+/-5.1% vs. control 17.1+/-2.3%). These results indicate that Ang II inhibits I-sus via the AT(1) receptor and activation of PKC. Ang II significantly prolonged action potential duration (APD) when the control APD was lengthened by a Ca2+ channel activator, BAY K8644. In myocytes with a relatively long APD, Ang II may prolong APD by inhibiting I-sus.